In addition to pervasive sadness, specific aspects of behavior and cognition are impaired in mood disorders, including selective attention, set-shifting and memory. There also is evidence that depressed individuals exhibit a mood congruent processing bias whereby they more readily process negatively toned information as compared to positively toned information. This cognitive pattern lends itself to evaluation with functional brain imaging, both in terms of identifying the anatomical correlates of the specific behavioral and cognitive differences as well as characterizing the effects of pharmacological manipulation. Attention and memory functions are closely tied to the cholinergic neurotransmitter system whereby drugs that enhance cholinergic function are found to enhance memory and attention while agents that interfere with normal cholinergic function impair performance on attention and memory tasks. Moreover, the cholinergic system is one of the neurotransmitter systems implicated in the pathophysiology of mood disorders. Evidence suggests that during major depressive episodes, the cholinergic system is hypersensitive to acetylcholine. Agents that enhance muscarinic cholinergic receptor function increase depressive symptoms in depressed subjects, and can produce symptoms of depression in healthy subjects. The preclinical literature more specifically implicates the muscarinic receptors and indicates that the use of muscarinic antagonists, in the context of animal models of depression, results in improvement in the behavioral analogs of depression. This on-going project investigates the role of cholinergic neurotransmission in the mood, behavioral and cognitive symptoms observed in the depressed phase of both major MDD and BD. These studies will evaluate the effects of the cholinergic antagonist, scopolamine, on mood in patient populations, as well as performance effects and alterations in neural activity in brain regions recruited to perform cognitive tasks. This approach is expected to reveal how neuromodulators influence processing in brain structures recruited to perform these tasks, and are expected to elucidate the role of cholinergic muscarinic receptors in the mood and cognitive symptoms observed in depression. The combined use of functional brain imaging and pharmacological manipulation to evaluate the role of neurotransmitter dysfunction in depression may direct us to potential therapeutic approaches. To date we have found that in healthy individuals, blocking cholinergic muscarinic function with scopolamine modulates performance on attention tasks but does so differentially based on the emotional content of the task stimuli with greater effects associated with sad stimuli. This result suggests that manipulation of cholinergic function in healthy individuals has highly selective, stimulus dependent effects, and results in the modulation of the salience of stimuli, including emotional stimuli. Moreover we identified complementary, stimulus specific effects on task performance when using an agent that increases cholinergic function, highlighting the bidirectional influence of acetylcholine. Aspects of these findings recently were published in Neuropsychopharmacology. We also have identified baseline performance differences between healthy controls and depressed patient groups that indicate differential processing of emotional stimuli in the context of attention tasks. Moreover, we have found that cholinergic manipulation alters performance differentially in healthy and depressed individuals based on the emotional content of the stimuli, supporting the hypothesis that acetylcholine is processing emotional stimuli differently in patients with mood disorders. This prediction was based on the hypothesis that the over-activity of the cholinergic system in depression results in an enhanced perceptual representation of negative stimuli that influences task performance, and that blocking overactive muscarinic receptors will diminish this effect. Importantly, we have preliminary findings showing differences between MDD and BD in both baseline task performance and in the differential responses to scopolamine, differences that again are based on the emotional content of stimuli. As the identification of performance differences between these patient groups has been elusive, this finding also has the potential to reveal important differences between these patient groups. The behavioral findings have guided functional imaging studies designed to elucidate the neurophysiological basis for observed differences between healthy individuals and patient groups, and for the differential responses to scopolamine. The observed behavioral effects are consistent with differences in the effects of scopolamine on the functional brain response observed to facial expressions in visual and emotional processing areas in the brain. The results suggest that an inherent bias towards processing face stimuli is cholinergically mediated, and that the cholinergic system differentially modulates stimuli based on the emotion content. We also are evaluating the role of the cholinergic system in the emotional processing bias observed in mood disorders, using tasks such as the affective shift task and a working memory task that requires matching face stimuli based on identify or emotion. We have observed preliminary data with the affective shift task that shows how task specific brain regions are altered by cholinergic modulation in brain areas that are important to emotional processing, including orbitofrontal cortex, insula and amygdala. The effects observed in these regions are consistent with changes in a behavioral emotional response bias, lending support to the hypothesis that acetylcholine has selective effects based on emotional valence of stimuli. The most important finding to date in the context of this project is that we have observed rapid and robust anti-depressant responses to scopolamine in our patient groups. This aspect of the work has the greatest potential for proving benefit to a large sector of the public suffering from mood disorders. Previously we reported that all patients who participated in our study and received intravenous infusions of scopolamine experienced dramatic antidepressant effects that were clinically significant by the next clinic visit, and over half of the group experienced full remission of their symptoms. The effects occurred quickly, within the 3 day period that came between sessions, far exceeding the typical three week period that traditional antidepressant agents require. In our estimation, scopolamine has the potential to become a new option for the clinical treatment of depression in MDD and BD, offering a medication that produces a more rapid response than traditional treatments offer. This year we completed a replication of these findings, which soon will appear in Biological Psychiatry. We observed equally rapid and robust antidepressant responses to scopolamine. We also have begun to look at sub-group responses, and have identified significant differences in response magnitude between men and women. Specifically, while both men and women show significant improvement in symptoms, women show a larger response than do men. This difference may be managed by increasing the dose of scopolamine for men, but this remains empirical. Aspects of these results have been presented at Biological Psychiatry, International Biological Psychiatry, the American College of Neuropsychopharmacology, Society for Neurosciences, and Human Brain Mapping.